This application claims priority from German Applications No. 198 27 311.8, filed on Jun. 19, 1998, 198 58 866.6 filed on Dec. 19, 1998 and 199 21 924.9 filed on May 12, 1999, the subject matter of each of which is hereby incorporated herein by reference.
1. Field of the Invention
The present invention is relates to a method for the homogeneous, catalytic, enantioselective hydrogenation of compounds of the general formula (I) 
in which
n is a whole number from 0 to 3,
Rxe2x95x90H, (C1-C18)-alkyl, (C6-C18)-aryl, (C7-C19)-aralkyl, (C3-C18)-heteroaryl, (C4-C18)-heteroaralkyl,
(C1-C8)-alkyl-(C6-C18)-aryl,
(C1-C8)-alkyl-(C3-C19)-heteroaryl, (C3-C8)-cycloalkyl,
(C1-C8)-alkyl-(C3-C8)-cycloalkyl,
(C3-C8)-cycloalkyl-(C1-C8)-alkyl, or signifies a carboxy protective group,
Rxe2x80x2xe2x95x90H, (C1-C18)-alkyl, (C6-C18)-aryl, (C7-C19)-aralkyl,
(C3-C18)-heteroaryl, (C4-C19)-heteroaralkyl,
(C1-C8)-alkyl-(C6-C18)-aryl,
(C1-C8)-alkyl-(C3-C19)-heteroaryl, (C3-C8)-cycloalkyl,
(C1-C8)-alkyl-(C3-C8)-cycloalkyl,
(C3-C8)-cycloalkyl-(C1-C8)-alkyl, which groups just cited can be substituted with (C1-C8)-acyl or (C1-C8)-alkyloxycarbonyl,
Xxe2x95x90O, CHRxe2x80x3, NRxe2x80x3, NNHRxe2x80x3,
Rxe2x80x3 can be xe2x95x90H, OH, Rxe2x80x2, (C1-C8)-alkoxy, (C2-C18)-alkoxyalkyl,
(C1-C18)-acyl, (C1-C18)-acyloxy and Rxe2x80x3 can assume different shapes for different positions in the molecule,
or R and Rxe2x80x2 or Rxe2x80x2 and Rxe2x80x3 or Rxe2x80x3 and R are connected to one another via a (C1-C4) bridge which can be singly or multiply substituted with linear or branched (C1-C8)-alkyl, (C1-C8)-acyl, (C1-C8)-alkoxy, (C2-C8)-alkoxyalkyl groups and/or can contain heteroatoms such as N, O, P, S in the ring,
with the aid of C2-symmetric ferrocenyl catalysts.
Furthermore, the invention relates to the use of the derivatives produced by the enantioselective hydrogenation of the invention as chiral intermediates in organic synthesis.
2. Background Information
The enantioselective introduction of stereogenic centers into organic molecules by homogeneously catalyzed hydrogenation is established for special applications on an industrial scale. The enantioselective products are valuable initial substances for the production of bioactive active substances.
The use of bisphosphine catalysts for the enantioselective, homogeneous, catalytic hydrogenation for the purpose just cited is well known (Burk et al., Tetrahedron 1994, 4399).
Knochel et al. (Chem. Eur. J. 1998, 4, 950-968), Hayashi et al. (J. Chem. Soc., Chem Commun. 1989, 495-496), and Ikeda et al. (Tetrahedron Lett. 1996, 4545-4548) describe Pd complexes with C2-symmetric ferrocenyl-(bis-tertiary phosphine) ligands. However, these complexes were used solely in asymmetric allylations. Their use as catalysts in enantioselective hydrogenation was not known up to the present.
Yamamoto at al. (Bull. Chem. Soc. Jpn. 1980, 53, 1132-1137) reported on the use of non C2-symmetric ferrocenyl-(bis-tertiary phosphine) ligands in enantioselective, homogeneous, catalytic hydrogenation. However, good excesses of enantiomers are obtained only very sporadically with these ligands.
DE 19 82 7311.8 and Kang et al. (Tetrahedron Lett. 1998, 39, 5523-5526) disclose C2-symmetric ferrocenyl complexes as suitable catalysts for the enantioselective hydrogenation of acetamido cinnamicacid derivatives.
It is an object of the present invention to provide a method for the homogeneous, catalytic, enantioselective hydrogenation of further, unsaturated systems with the aid of C2-symmetric ferrocenyl catalysts.
The term xe2x80x9cmultiple bondsxe2x80x9d denotes in the framework of the invention double bonds between a carbon atom and another carbon atom or oxygen atom or nitrogen atom.
This objective is achieved by a method using C2-symmetric ferrocenyl catalysts as described hereinbelow.
As a result of the fact that for the homogeneous, catalytic, enantioselective hydrogenation of compounds of the general formula (I) 
in which
n is a whole number from 0 to 3,
Rxe2x95x90H, (C1-C18)-alkyl, (C6-C18)-aryl, (C7-C19)-aralkyl, (C3-C18)-heteroaryl, (C4-C19)-heteroaralkyl,
(C1-C8)-alkyl-(C6-C18)-aryl,
(C1-C8)-alkyl-(C3-C19)-heteroaryl, (C3-C8)-cycloalkyl,
(C1-C8)-alkyl-(C3-C8)-cycloalkyl,
(C3-C8)-cycloalkyl-(C1-C8)-alkyl,
or signifies a carboxy protective group,
Rxe2x80x2xe2x95x90H, (C1-C18)-alkyl, (C6-C18)-aryl, (C7-C19)-aralkyl,
(C3-C18)-heteroaryl, (C4-C19)-heteroaralkyl,
(C1-C8)-alkyl-(C6-C18)-aryl,
(C1-C8)-alkyl-(C3-C19)-heteroaryl, (C3-C8)-cycloalkyl,
(C1-C8)-alkyl-(C3-C8)-cycloalkyl,
(C3-C8)-cycloalkyl-(C1-C8)-alkyl, which groups just cited can be substituted with (C1-C8)-acyl or (C1-C8)-alkyloxycarbonyl,
Xxe2x95x90O, CHRxe2x80x3, NRxe2x80x3, NNHRxe2x80x3,
Rxe2x80x3 can be H, OH, Rxe2x80x2, (C1-C18)-alkoxy, (C2-C18)-alkoxyalkyl, (C1-C18)-acyl, (C1-C18)-acyloxy and Rxe2x80x3 can assume different shapes for different positions in the molecule,
or R and Rxe2x80x2 or Rxe2x80x2 and Rxe2x80x3 or Rxe2x80x3 and R are connected to one another via a (C1-C4) bridge which can be singly or multiply substituted with linear or branched (C1-C8)-alkyl, (C1-C8)-acyl, (C1-C8)-alkoxy, (C2-C8)-alkoxyalkyl groups and/or can contain heteroatoms such as N, O, P, S in the ring,
catalysts of the general formula (II) 
are used
in which
R1, R2 signify, independently of one another, H, NR6R7, SR6,
(C1-C18)-alkyl, (C1-C18)-alkoxy, (C2-C18)-alkoxyalkyl,
(C1-C18)-acyloxy, (C6-C18)-aryl, (C7-C19)-aralkyl,
(C3-C18)-heteroaryl, (C4-C19)-heteroaralkyl,
(C1-C8)-alkyl-(C6-C18)-aryl,
(C1-C8)-alkyl-(C3-C19)-heteroaryl, (C3-C8)-cycloalkyl,
(C1-C8)-alkyl-(C3-C8)-cycloalkyl,
(C3-C8)-cycloalkyl-(C1-C8)-alkyl,
or R1 and R2 are connected via a (C3-C7)-carbocycle which can be singly or multiply substituted with linear or branched (C1-C8)-alkyl, (C1-C8)-acyl, (C1-C8)-alkoxy, (C2-C8)-alkoxyalkyl and/or can contain heteroatoms such as N, O, P, S in the ring,
R3 signifies (C2-C18)-alkyl, (C1-C18)-alkoxy,
(C2-C18)-alkoxyalkyl, (C1-C18)-acyloxy, (C6-C18)-aryl,
(C7-C19)-aralkyl, (C3-C18)-heteroaryl, (C4-C19)-heteroaralkyl,
(C1-C8)-alkyl-(C6-C18)-aryl,
(C1-C8)-alkyl-(C3-C19)-heteroaryl, (C3-C8)-cycloalkyl,
(C1-C8)-alkyl-(C3-C8)-cycloalkyl,
(C3-C8)-cycloalkyl-(C1-C8)-alkyl,
R4 signifies (C1-C18)-alkyl, (C6-C18)-aryl,
(C3-C18)-heteroaryl, (C1-C8)-alkyl-(C6-C18)-aryl,
(C1-C8)-alkyl-(C3-C19)-heteroaryl, (C3-C8)-cycloalkyl,
(C1-C8)-alkyl-(C3-C8)-cycloalkyl,
R5 signifies H or a group B-X-Z in which B is a residue selected from the groups CR82, NR8, O, S, and SiR82, X is a spacer such as, e.g., 1,4xe2x80x2-biphenyl, 1-, 2-ethylene, 1-, 3-propylene, PEG-(2-10) and Z signifies a group bound to a polymer via a functional group such as, e.g., the Oxe2x80x94, NHxe2x80x94, COOxe2x80x94, CONHxe2x80x94, ethenylxe2x80x94, NHCONHxe2x80x94, OCONHxe2x80x94 or NHCOOxe2x80x94, or the groups R5 of the two cyclopentadienyl rings are connected to each other via an a, xcex1, xcfx89-(C2-C4)-alkylene bridge,
R6, R7 signify, independently of one another, H, (C1-C18)-alkyl,
(C1-C18)-alkoxy, (C2-C18)-alkoxyalkyl, (C1-C18)-acyl,
(C6-C18)-aryl, (C7-C19)-aralkyl, (C3-C18)-heteroaryl,
(C4-C19)-heteroaralkyl, (C1-C8)-alkyl-(C6-C18)-aryl,
(C1-C8)-alkyl-(C3-C19)-heteroaryl, (C3-C8)-cycloalkyl,
(C1-C8)-alkyl-(C3-C8)-cycloalkyl,
(C3-C8)-cycloalkyl-(C1-C8)-alkyl,
or R6 and R7 are connected via a (C3-C7)-carbocycle which can be substituted simply or multiply with linear or branched (C1-C8)-alkyl, (C1-C8)-acyl, (C1-C8)-alkoxy, (C2-C8)-alkoxyalkyl and or can contain heteroatoms such as N, O, P, S in the ring,
R8 signifies H, (C1-C18)-alkyl
and M is a metal atom or metal ion of subgroup 7 or 8 such as, e.g., Co, Ni, Rh, Ru, Ir, Pd, Re or Pt,
the desired hydrogenated derivatives are obtained in a manner which could not have been foreseen in good to very good yields and with good to very good excesses of enantiomers.
Compounds of the general formula (II) are preferably used as catalysts in which
R1 , R2 signify, independently of one another, H, N (C1-C8)-alkyl2, NH (C1-C8)-acyl, N (C1-C8)-acyl2, O (C1-C8)-acyl, (C1-C8)-alkyl, (C1-C8)-alkoxy,
(C2-C8)-alkoxyalkyl, (C3-C7)-cycloalkyl
(C6-C18)-aryl,
R3 signifies (C3-C7)-cycloalkyl, (C6-C18)-aryl,
R4 signifies (C1-C8)-alkyl, (C3-C7)-cycloalkyl, (C6-C18)-aryl,
R5 signifies H.
The use of compounds of general formula (II) as catalysts is quite especially preferred in which
R1, R2 signify, independently of one another, H, O (C1-C8)-acyl, N (C1-C8)-alkyl2, (C1-C8)-alkyl,
R3 signifies (C6-C18)-aryl,
R4 signifies phenyl,
R5 signifies H.
The method in accordance with the invention can be carried out in an advantageous manner at a temperature between 0xc2x0 C. and 150xc2x0 C., preferably between 20xc2x0 C. and 80xc2x0 C.
The hydrogen pressure should be between 10 kPa and 10000 kPa, preferably between 50 kPa and 8000 kPa during the reaction.
All solvents familiar to those skilled in the art can be used as solvents, provided that they do not disturb the result as regards yield and chiral induction. Ethers such as THF, DME, MTBE, alcohols such as MeOH, EtOH, propanol, butanol are preferably used.
The making available of the C2-symmetric catalysts can take place according to DE 19 82 7311.8.
The ferrocenyl catalysts exhibit excellent values during the homogeneous, enantioselective hydrogenation, as shown in Table 1.
The catalytic concentration is already very low, with 1% in the cited examples. However, it can be lowered further for industrial application. Both of these facts are very advantageous for the application of the ligands of the invention on an industrial scale since the expenses for the products obtained according to this method are correspondingly lower and a higher economical use is guaranteed than when using ligand systems of the state of the art.
The R5 group in the complexes can be used, among other things, to bond the complexes of the invention to a polymeric matrix such as, e.g., a linear PMMA, polystyrene or PEG as well as to a non-linear dendrimer. The bonding of the R5 group to the cyclopentadienyl ring of the complex of the invention is variable as regards the free positions and the ring. Therefore, the bonding of the polymer to one ring is sufficient. All groups considered suitable by the skilled artisan for this purpose can be used. A suitable survey for the molecular enlargement of complex catalysts is found in Tetrahedron Asymmetry 1998, 9, 691-696. The R5 group preferably consists of the arrangement B-X-Z in which B is a residue selected from the group CR82, NR8, O, S, SiR82, X is a spacer such as, e.g., 1,4xe2x80x2-biphenyl, 1-, 2-ethylene, 1-, 3-propylene, PEG-(2-10) and Z is a functional group such as, e.g., the Oxe2x80x94, NHxe2x80x94, COOxe2x80x94, CONH, ethenyl-, NHCONHxe2x80x94, OCONHxe2x80x94 or NHCOOxe2x80x94 function bound to a polymer like the one described above. Alternatively, the R5 groups of the two cyclopentadienyl rings can be connected to each other via an xcex1,xcfx89-(C2-C4)-alkylene bridge.
The fact that in addition to the acetamido cinnamic-acid derivatives, other unsaturated compounds can be hydrogenated with values which are quite high in some instances, with the C2-symmetric ferrocenyl complexes had not been known previously in the art. It is all the more surprising but not less advantageous that even compounds of type (I) can be reacted enantioselectively.
Methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl or octyl up to a group comprising 18 C atoms together with all of its bonding isomers can be considered as linear or branched (C1-C18)-alkyl. The (C1-C18)-alkoxy group corresponds to the (C1-C18)-alkyl, provided that the latter is connected to the molecule via an oxygen atom. (C2-C18)-alkoxyalkyl denotes groups in which the alkyl chain is interrupted by at least one oxygen function and two oxygen atoms are not be connected to one another thereby. The number of carbon atoms indicates the total number of the carbon atoms contained in the group.
The groups just described can be substituted singly or multiply with halogens and/or groups containing Nxe2x80x94, Oxe2x80x94, Pxe2x80x94, S atoms. These are, in particular, alkyl groups of the type cited above which comprise one or several of these heteroatoms in their chain or which are bound to the molecule via one of these heteroatoms. That which was stated above applies correspondingly for the (C1-C8)-alkyl groups for an alkyl group containing at most 8 C atoms.
The term (C3-C8)-cycloalkyl denotes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl groups, etc. They can be substituted with one or several halogens and/or groups containing, N, O, P, S atoms and/or comprise groups containing N, O, P, S atoms in the ring such as, e.g., 1-, 2-, 3-, 4-piperidyl, 1-, 2-, 3-pyrrolidinyl, 2-, 3-tetrahydrofuryl, 2-, 3-, 4-morpholinyl.
A (C3-C8)-cycloalkyl-(C1-C8)-alkyl group designates a cycloalkyl group as presented above which is bound to the molecule via an alkyl group as indicated above.
(C1-C18)-acyloxy signifies in the framework of the invention an alkyl group as defined above with a maximum of 18 C atoms which is bound to the molecule via a COOxe2x80x94 function. The same applies in a corresponding manner to (C1-C8)-acyloxy.
(C1-C18)-acyl signifies in the framework of the invention an alkyl group as defined above with a maximum of 18 C atoms which is bound to the molecule via a COxe2x80x94 function. The same applies in a corresponding manner to (C1-C8)-acyl.
(C1-C8)-alkyloxycarbonyl group signifies in the framework of the invention an alkyl group as defined above with a maximum of 8 C atoms which is bound to the molecule via an OCOxe2x80x94 function.
The term (C6-C18)-aryl group denotes an aromatic group with 6 to 18 C atoms. This includes, in particular, compounds such as phenyl groups, naphthyl groups, anthryl groups, phenanthryl groups and biphenyl groups, which can optionally be substituted with (C1-C8)-alkoxy, NR6R7, (C1-C8)-acyl, (C1-C8)-acyloxy.
A (C7-C19)- aralkyl group is a (C6-C18)-aryl group bound to the molecule via a (C1-C8)-alkyl group.
A (C3-C18)-heteroaryl group designates in the framework of the invention a five- , six- or seven-member, aromatic ring system consisting of 3 to 18 C atoms which comprises heteroatoms such as, e.g., nitrogen, oxygen or sulfur in the ring. Groups such as 1-, 2-, 3-furyl, such as 1-, 2-, 3-pyrrolyl, 1-, 2-, 3-thienyl, 2-, 3-, 4-pyridyl, 2-, 3-, 4-, 5-, 6-, 7-indolyl, 3-, 4-, 5-pyrazolyl, 2-, 4-, 5-imidazolyl, acridinyl, quinolinyl, phenanthridinyl, 2-, 4-, 5-, 6-pyrimidinyl are considered in particular as such heteroaromatic compounds.
The term (C4-C19)-heteroaralkyl denotes a heteroaromatic system corresponding to the (C7-C19)-aralkyl group.
The term xe2x80x9ccarboxy protective groupxe2x80x9d denotes a group as described in J. Jones, The Chemical Synthesis of Peptides, Oxford Science Pub., 1991, p. 33 ff.
Fluorine, chlorine, bromine and iodine can be considered as halogens.
The term xe2x80x9csaltsxe2x80x9d denotes ionic addition compounds of strong acids such as HCl, HBr, H2SO4, H3PO4, CF3OOH, p-toluene sulfonic acid, methane sulfonic acid and the molecule under consideration.
PEG signifies polyethylene glycol.
The concept xe2x80x9cenantiomer-enrichedxe2x80x9d denotes in the framework of the invention an amount of an enantiomer in the mixture with its optical antipode in a range of  greater than 50% and  less than 100%.
The concept xe2x80x9cdiastereomer-enrichedxe2x80x9d denotes the excess of a diastereomer relative to one or several others.
The naming of the complexes and ligands in accordance with the invention comprises in the framework of the invention all possible diastereomers and even the two optical antipodes of a particular diastereomer should be named.
The term xe2x80x9cpolymersxe2x80x9d denotes in the framework of the invention a polymeric matrix such as, e.g., linear PMMA, polystyrene or PEG as well as non-linear dendrimers.